PDGFR blockade is a rational and effective therapy for NPM-ALK–driven lymphomas

Abstract

Anaplastic Large Cell Lymphoma (ALCL) is a Non-Hodgkin lymphoma found in children and young adults with poor survival rates. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK triggered lymphoma growth are still not entirely clear. Here we show that the AP-1 proteins cJun and JunB promote lymphoma development and tumor dissemination in a murine NPM-ALK lymphomagenesis model via transcriptional regulation of PDGFRB. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor in transplanted NPM-ALK tumors. Remarkably, inhibition of PDGFRs in a late stage patient with refractory NPM-ALK-positive ALCL resulted in complete and sustained remission within 10 days of treatment. Our data identify PDGFRB as novel cJun/JunB target that could be utilized for a highly effective therapy to cure ALCL. 3ALCLs are T-cell lymphomas 1,2 that comprise 10-20% of all Non-Hodgkin's lymphoma cases in children and 3% in adults 3 . About half of ALCL cases are positive for NPM-ALK fusion proteins caused by t(2;5)(p23;q35) translocation 4 . ALK translocations or point mutations have also been described in DLBCLs (diffuse large B-cell lymphomas) and in several nonlymphoid neoplasms [5][6][7][8] . Inhibition of ALK fusion proteins by specific compounds such as crizotinib showed promising clinical responses in ALCL and NSCLC (non-small cell lung cancer) 9,10 . However, ALK mutations conferring resistance to crizotinib have also been reported 11 .Recent studies have linked NPM-ALK expression to induction of AP-1 transcription factors JunB and cJun 12,13 . To investigate their role in NPM-ALK-driven T-cell lymphomas, we conditionally deleted cJun and/or JunB in T-cells of transgenic mice carrying the human NPM-ALK fusion-tyrosine-kinase under the control of the murine CD4-promotor 14 (CD4-NPM-ALK) (Fig. 1a). Gene deletion was confirmed by DNA genotyping (data not shown), real-time PCR, Western blotting and immunohistochemistry (IHC) (Suppl. (Fig.1b), however, inactivation of both, cJun and JunB, in CD4-NPM-ALK-CD4 ΔΔJun mice resulted in significantly prolonged survival (Fig. 1b). CD4-NPM-ALK-CD4 ΔΔJun lymphomas showed markedly reduced proliferation and significantly increased apoptosis when compared to CD4-NPM-ALK lymphomas ( Fig. 1c; Suppl. Fig. S2a,b). Consistently, (Fig. 2d) suggesting a transcriptional regulation of PDGFRB by Jun proteins. Consistently, AP-1 consensus sequences were identified within the murine PDGFRB promoter and first intron that were conserved among other species (Suppl. Fig. S3b,c) 15,16 . Moreover, analysis of ENCODE transcription factor binding tracks revealed binding of cJun and JunB to the PDGFRB intronic AP-1 site in the human K562 leukemia cell line (Suppl. Fig. S3d) 15,17 . CD4-NPM-ALK-CD4EMSA analysis of nuclear extracts from NPM-ALK lymphomas demonstrated AP-1 DNA ...

Endogenous dendritic cells from the tumor microenvironment support T-ALL growth via IGF1R activation

“…Furthermore, PDGF receptors are up-regulated in mature T-cell lymphomas (53)(54)(55)(56), and a translocation involving PDGFRB has been identified in a T-ALL patient (53). To our knowledge, we provide the first evidence that PDGFRβ is up-regulated preferentially in ETP T-ALLs.…”

“…Thus, inappropriate maintenance of this growth factor receptor may contribute to tumorigenesis of the immature and aggressive ETP T-ALL subset. Importantly, remission of a patient with refractory anaplastic large cell lymphoma was recently achieved with a PDGFRβ inhibitor, imatinib (55), highlighting the potential of targeting PDGFRβ in other T-cell malignancies. However, our studies demonstrate that DCs promote T-ALL survival through IGF1R activation in the absence of PDGFRβ signaling.…”

Imaging of Platelet-Derived Growth Factor Receptor β Expression in Glioblastoma Xenografts Using Affibody Molecule111In-DOTA-Z09591

“…The use of these TKIs improves survival of patients with hepatocellular carcinoma, gastrointestinal stromal tumors, and renal cell carcinoma. Although TKIs generally target several tyrosine kinases, research suggests that PFDGRb is a key target for imatinib in several malignancies (11)(12)(13). There is a well-recognized unmet clinical need for biomarkers for selection of patients who might benefit from such therapy (14).…”

Aspects moléculaires des lymphomes T périphériques (1)

“…L'activation des voies ERK et mTOR entraîne la transcription des gènes codant les facteurs Jun et JunB, qui conduit à la surexpression dans certains cas du PDGFR. L'inhibition du PDGFR par l'imatinib 5 augmente la survie des souris transgéniques NPM-ALK et agit en synergie avec les inhibiteurs de ALK [64]. L'expression de NPM-ALK est associée à une répression du gène codant le miARN miR-29a, ce qui conduit à la surexpression de la protéine anti-5 L'imatinib (ou Glivec) est un inhibiteur pharmacologique qui entre en compétition avec l'adénosine triphosphate (ATP) dans la poche des kinases BCR-ABL (leucémie myéloïde chronique), ckit, PDGFR.…”